PROSTVAC in Combination With Nivolumab in Men With Prostate Cancer

Background:

- Immune checkpoint inhibitors interfere with the immune system s autoregulatory
mechanisms, allowing for a potentially expanded and prolonged T-cell response with the
possibility of greater antitumor effects.

- Nivolumab is a fully human IgG4 monoclonal antibody that targets the PD-1 protein.
Specifically, the antibody binds to the PD-1 receptor and blocks its interaction with
PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune
response, including anti-tumor immune response.

- PROSTVAC (developed by the National Cancer Institute [NCI] and licensed to Bavarian
Nordic Immunotherapeutics, Mountain View, CA) is a therapeutic cancer vaccine for
prostate cancer. Early studies have demonstrated immunologic efficacy and suggested
clinical benefit. A phase III trial has completed accrual.

- A previous study combining the immune checkpoint inhibitor ipilimumab and PROSTVAC
suggested greater efficacy than PROSTVAC alone. Additional studies have demonstrated the
potential efficacy of immunologic combination therapy with the immune checkpoint
inhibitor nivolumab.

- This study will aim to evaluate the impact of the combination of PROSTVAC and the immune
checkpoint inhibitor nivolumab on the tumor microenvironment focusing on immune cell
infiltration as the primary endpoint.

- US-MRI imaging technology will be employed to sample the tumor before treatment and
after radical prostatectomy.

- The findings from this study could serve as the basis for future studies with this
combination in this population of patients and more advanced disease.

Objectives:

- Safety (For castration resistant prostate cancer (CRPC) lead-in cohort)

- Evaluate changes in T-cell infiltration in the tumor after neoadjuvant treatment with
PROSTVAC and nivolumab, relative to changes seen in a phase 2 trial with PROSTVAC alone
in the neoadjuvant setting- NCT02153918 (For the neoadjuvant cohort).

Eligibility:

- Patients must have histopathological documentation of adenocarcinoma of the prostate
prior to starting this study and evaluable biopsy tissue (e.g., unstained slides or
blocks) available for analysis.

- For the castration resistant lead in cohort, if histopathological documentation is
unavailable, a rising PSA and a clinical course consistent with prostate cancer would be
acceptable.

- Patients must have a performance status of 0 to 1 according to the ECOG criteria.

- Hematological eligibility parameters (within 16 days of starting therapy):

- Granulocyte count 1,500/mm^3

- Platelet count 100,000/mm^3

- Hgb greater than or equal to 8 g/dL

- Biochemical eligibility parameters (within 16 days of starting therapy):

- Hepatic function: Bilirubin < 1.5 mg/dl (OR in patients with Gilbert's syndrome,
total bilirubin less than or equal to 3.0 mg/dL), AST and ALT less than or equal to
2.5 times upper limit of normal.

- Creatinine less than or equal to 1.5 X ULN

Design:

- The primary focus of this study will be to evaluate PROSTVAC and nivolumab in the
neoadjuvant setting.

- Lead-in cohort evaluating the safety and tolerability of this combination in the
castration resistant setting (CRPC cohort)

- Following this lead-in cohort in the CRPC setting, we will enroll a cohort in the
neoadjuvant setting evaluating the combination of PROSTVAC and nivolumab.

- The lead-in safety cohort will require 10 patients and the neoadjuvant cohort will
require 17 evaluable patients. In order to allow for a small number of inevaluable
patients, the accrual ceiling will be set to 29 patients.

- INCLUSION CRITERIA:

For all cohorts except the CRPC lead in cohort, patients must have histopathological
documentation of adenocarcinoma of the prostate prior to starting this study and evaluable
biopsy tissue (e.g., unstained slides or blocks) available for analysis. If evaluable
tissue is not available, the patient must agree to undergo a pre-vaccination prostate
biopsy on study. For the CRPC lead in cohort, if histopathological documentation is
unavailable, a rising PSA and a clinical course consistent with prostate cancer would be
acceptable.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of PROSTVAC in combination with nivolumab, ipilimumab
or both in patients <18 years of age, children are excluded from this study, but will
be eligible for future pediatric trials.

- ECOG performance status of 0 or 1.

- Patients must not have other active invasive malignancies within the past 2 years
(with the exception of non-melanoma skin cancers) (for CRPC cohort only).

- Patients must be willing to travel to the study site for follow-up visits

- All patients who have received prior vaccination with vaccinia virus (for smallpox
immunization) must not have a history of adverse reaction to the vaccine.

- The effects of PROSTVAC in combination nivolumab, ipilimumab or both on the developing
human fetus are unknown. For this reason men must agree to use adequate contraception
(abstinence, vasectomy) or female partner must use (intrauterine device (IUD),
hormonal [birth control, pills, injections, or implants], tubal ligation] prior to
study entry and for up to 5 months after the last dose.

- Patients must understand and sign informed consent that explains the neoplastic nature
of their disease, the procedures to be followed, the experimental nature of the
treatment, alternative treatments, potential risks and toxicities, and the voluntary
nature of participation.

- Patients must have normal organ and marrow function as defined below:

- hemoglobin greater than or equal to 8 g/dL

- granulocytes greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin < 1.5 mg/dL (or less than or equal to 3.0 mg/dL in patients with
Gilbert syndrome)

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of
normal

- creatinine less than or equal to 1.5 X ULN

- For the lead in cohort:

- Castrate testosterone level (<50ng/dl or 1.7nmol /L)

- Progressive disease at study entry defined as one or more of the following
criteria occurring in the setting of castrate levels of testosterone:

- Radiographic progression defined as any new or enlarging bone lesions or
growing lymph node disease, consistent with prostate cancer OR

- PSA progression defined by sequence of rising values separated by >1 week (2
separate increasing values over a minimum of 2ng/ml (PCWG2 PSA eligibility
criteria). If patients had been on flutamide, PSA progression is documented
4 weeks or more after withdrawal. For patients on bicalutamide or nilutamide
disease progression is documented 6 or more weeks after withdrawal.

- Patients must agree to continue to continuation of androgen deprivation therapy
(ADT) with a gonadotropin-releasing hormone agonist/antagonist or bilateral
orchiectomy

- For all other cohorts:

- Patients must be a surgical candidate for radical prostatectomy based on standard
workup of PSA, biopsy results, and if necessary supplemental imaging.

- Patients must have chosen radical prostatectomy as their definitive treatment of
choice for management of their prostate cancer.

- No systemic steroid or steroid eye drop use within 2 weeks prior to initiation of
experimental therapy. Limited doses of systemic steroids to prevent IV contrast,
allergic reaction or anaphylaxis (in patients who have known contrast allergies)
are allowed.

EXCLUSION CRITERIA:

- Prior splenectomy.

- The recombinant vaccinia vaccine should not be administered if the following apply to
either recipients or, for at least 3 weeks after vaccination, their close household
contacts (Close household contacts are those who share housing or have close physical
contact):

- persons with active or a history of eczema or other eczematoid skin disorders

- those with other acute, chronic or exfoliative skin conditions (e.g., atopic
dermatitis, burns, impetigo, varicella zoster, severe acne or other open rashes
or wounds) until condition resolves

- pregnant or nursing women; children under 3 years of age

- Patients should have no evidence, as listed below, of being immunocompromised:

- HIV positivity due to the potential for decreased tolerance and risk for severe
side effects.

- Hepatitis B or C positivity.

- Concurrent use of systemic steroids or steroid eye drops. This is to avoid
immunosuppression which may lead to potential complications with vaccinia (priming
vaccination). Nasal, topical or inhaled steroid use is permitted.

- Patients with known allergy to eggs or to compounds with a similar chemical or
biologic composition to PROSTVAC, ipilimumab or nivolumab.

- No prior immune checkpoint inhibitors (e.g., anti-CTLA4, anti-PD-1 or anti-PDL1) are
allowed.

- Other serious intercurrent illness.

- Patients with a history of unstable or newly diagnosed angina pectoris, recent
myocardial infarction (within 6 months of enrollment) or New York Heart Association
class II IV congestive heart failure.

- Patients with significant autoimmune disease that is active or potentially life
threatening if activated.

- Patients with clinically significant cardiomyopathy requiring treatment.

- Patients with ongoing toxicities related to prior therapies targeting T cell
coregulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or
anti-CTLA-4 antibody are excluded

- No transfusion of blood or blood products within 2 weeks and no G-CSF or GM-CSF within
2 weeks prior to initiations of experimental therapy.

- Contraindication to biopsy or prostatectomy (for sequential neoadjuvant cohorts only):

- Bleeding disorders

- Artificial heart valve

- PT/PTT greater than or equal to 1.5 in patients not taking anticoagulation.
Patients on anticoagulation (e.g. enoxaparin, oral anticoagulants) are eligible
regardless of PT/PTT. Prior to biopsy, anticoagulation will be held per standard
practice.

- For patients with localized prostate cancer contraindication to MRI:

- Patients weighing >136 kilograms (weight limit for the scanner tables)

- Allergy to MR contrast agent

- Patients with pacemakers, cerebral aneurysm clips, shrapnel injury or implantable
electronic devices

- History of radiation proctitis (for lead-in CRPC cohort only)